Since the discovery of the histone deacetylases SIRT1, it has become clear that modifying the structure of chromatin has a beneficial effect in lifespan. Considering that there are many proteins endowed with chromatin remodeling activity (histone aceyltransferases (HATs), classical histone deacetylases (HDACs), histone methyltransferases, histone demethylases, and others), it is likely that at least some of them have either beneficial or detrimental effects not only in lifespan but also in healthspan. Unfortunately, knocking down any of these proteins is embryonic lethality. To overcome this negative outcome we decided to tweak the structure of chromatin to ask whether such alterations could be used for healthspan benefits. To achieve this goal we generated a transgenic mouse that expresses the CH3 domain of the p300 (CH3p300). This domain was chosen since it is bound by a large number of transcription factors as well by HDAC1, and functions as a dominant negative. The animals are born normal and do not have significant phenotypic changes either at young age or in old age (20 month old). However, when challenged with a high fat diet, the CH3p300 animals accumulate 30% less fat compared to wild-type littermates. We hypothesize that that expression of CH3p300 diminishes deleterious outcomes associated with a high fat diet by regulating the metabolic transcriptome. Using our innovative mouse model we propose to address the following aims: Specific Aim 1: To determine whether the CH3p300 transgenic mice display chromatin signatures associated with resistance to high fat-induced obesity and hepatic steatosis. We will map global changes in chromatin modifications or marks using ChIP-sequencing of liver tissue from CH3p300 and wild-type mice that are fed a normal chow or a high fat diet, and verify these data using ChIP-qPCR of selected targets. Specific Aim2: To determine the impact of the global chromatin marks on gene transcription. We will generate gene expression profiles of livers from CH3p300 and wild-type mice fed a high fat diet. These data will be compared to the ChIP-Seq data generated in Aim 1. Impact of the studies proposed to the field of Aging: If our hypothesis is confirmed, the knowledge obtained from our experiments may help design in the future new therapeutic approaches for improving healthspan in older adults as HAT, HDAC, and methyltransferase inhibitors are already in clinical trials for several diseases. PUBLIC HEALTH RELEVANCE: Maintaining healthspan till old age is a goal of mankind, but there are virtually no animal models to study it. We have generated transgenic mice that express the CH3 domain of the p300 histone acetyltransferase. When challenged with a high fat diet, the transgenic mice accumulate less weight and less body fat than wild type littermates. The goal of this proposal is to determine whether chromatin alterations resulting from expression of CH3p300 maintain a healthy lifespan in spite of the metabolic stress induced by a high fat diet.